Connecting genetic variation with gene expression and other phenotypes is a major goal of genomic science. Gene expression patterns vary widely among different cell and tissue types, and also regionally within a tissue. The impact of genetic variation on gene expression patterns is thus expected to differ substantially between tissues. The Genotype-Tissue Expression (GTEx) is establishing resource databases to enable comprehensive analysis of tissue gene expression profiles and their connection with individual genotypes. Most variants linked to individual variation in human gene expression lie in non-coding regions of the genome; of these, a proportion is expected to directly impact gene regulation through perturbation of regulatory DNA regions. Systematic understanding of the impact of genetic variation on gene expression will thus require both comprehensive delineation of regulatory DNA, and an understanding of the degree to which actuation of individual regulatory regions varies at the population level. In this proposal we aim to empower the central goal of GTEx -- connecting genotype to gene expression patterns -- for diverse human tissues by comprehensively delineating regulatory DNA at very high resolution, and systematically identifying genetic variants that impact its function through abrogation of regulatory factor binding and perturbation of local chromatin architecture. We will apply high-resolution genome-scale mapping of DNaseI hypersensitive sites to comprehensively delineate regulatory DNA within tissue samples from a multi-ethnic population accrued by the GTEx project. We will also apply genomic DNaseI footprinting at genome-scale and in a targeted fashion to map transcription factor occupancy within regulatory DNA at nucleotide resolution.